International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer Makoto Shinoto, MD,*,y,z Shigeru Yamada, MD, PhD,* Kotaro Terashima, MD, PhD,z Shigeo Yasuda, MD, PhD,* Yoshiyuki Shioyama, MD, PhD,y Hiroshi Honda, MD, PhD,z Tadashi Kamada, MD, PhD,* Hirohiko Tsujii, MD, PhD,* and Hiromitsu Saisho, MD, PhD,x the Working Group for Pancreas Cancer *Hospital of Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan; yIon Beam Therapy Center, SAGA HIMAT Foundation, Tosu, Japan; z Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and xDepartment of Internal Medicine and Clinical Oncology, Kaken Hospital, Chemotherapy Research Institute, Chiba, Japan Received Sep 17, 2015, and in revised form Dec 14, 2015. Accepted for publication Dec 15, 2015.
Summary Carbon ion radiation therapy is a unique external radiation therapy that has an excellent dose conformity and higher biological effectiveness compared with conventional radiation therapy. We performed a dose escalation study of carbon ion radiation therapy plus concurrent gemcitabine in 72 patients with locally advanced
Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m2 under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, doselimiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion
Reprint requests to: Makoto Shinoto, MD, SAGA HIMAT Foundation, Ion Beam Therapy Center, 3049 harakoga-machi, Tosu, Saga, 841-0071 Japan. Tel: (þ81) 942-81-1897; E-mail: [email protected] This study was supported by the Research Project with Heavy Ions at the National Institute of Radiological Sciences-Heavy Ion Medical Accelerator in Chiba. Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e7, 2016 0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.12.362
AcknowledgmentdThe authors thank the members of The Working Group for Pancreatic Cancer, Takehide Asano, Taketo Yamaguchi, Hodaka Amano, Takeshi Ishihara, Masayuki Otsuka, Masamichi Matsuda, Osamu Kainuma, Akihiro Funakoshi, Junji Furuse, Toshio Nakagori, Takuji Okusaka, Hiroshi Ishii, Tatsuya Nagakawa, Shinichiro Takahashi, Shoichi Hishinuma, Masafumi Nakamura, Hirofumi Saito, Kiyoshi Ohara, Shinichi Ohkawa, and Masahiro Hiraoka, for their constructive discussion and precious advice.
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pancreatic cancer. Carbon ion radiation therapy with full-dose gemcitabine was considered well tolerated and effective.
RT was found to be 1000 mg/m2. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m2) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer. Ó 2016 Elsevier Inc. All rights reserved.
Introduction Pancreatic cancer is one of the most lethal cancers, and it is the fourth leading cause of death from cancer in Japan. At this time surgery is the only path to cure, but only a small number of patients present with resectable disease at the time of diagnosis. The majority of patients present with advanced unresectable disease. After the introduction of gemcitabine as a key drug, the prognosis for patients with pancreatic cancer improved slightly (1, 2). In localized pancreatic cancer, local control using radiation therapy is expected to have an impact on survival. However, radiation therapy has often been used suboptimally in pancreatic cancer. The sensitivity of the organs in the upper abdomen has limited the radiation dose to levels that are ineffective against gross disease. In addition, gemcitabine is a potent radiation sensitizer, and its concurrent use with radiation therapy has been limited by toxicity (3). Compared with photon beams, carbon ion beams offer improved dose distribution, enabling us to concentrate a sufficient dose within a target volume while minimizing the dose in the surrounding normal tissue. In addition, carbon ions (being heavier than protons) provide greater biological effectiveness, which increases with depth, reaching the maximum at the end of the beam’s range. This is an ideal property of cancer therapy in which a local type of therapy, such as carbon ion radiation therapy (C-ion RT), is needed. Thus, we hypothesized that an intensification of local therapy using C-ion RT combined with systemic therapy using gemcitabine would result in better local control and survival for locally advanced pancreatic cancer (LAPC). We performed a dose escalation study to determine the maximum tolerated C-ion RT and gemcitabine dose delivered concurrently and to estimate the local effect and survival with this regimen.
Methods and Materials Patient eligibility Patients were eligible for this study if they fulfilled the following criteria: histologically or cytologically confirmed invasive ductal carcinomas of the pancreas with unresectable LAPC; presence of either measurable or evaluable
disease, but the lesion does not exceed 15 cm in diameter; age 75 years or younger; Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate organ function, defined as an absolute leukocyte count 4000/ mm3, platelet count 100,000/mm3, hemoglobin 10 g/ dL, serum creatinine 1.5 mg/dL, creatinine clearance 60 mL/min, serum bilirubin 2.0, and serum aspartate aminotransferase and alanine aminotransferase 2.5 times the upper limit of normal range for the institution. Unresectability was defined by radiographic evidence of encasement of the celiac axis, the superior mesenteric artery, or both (involving 180 ) or by occlusion of the superior mesenteric vein, portal vein, or both confluences, which were reviewed by the Working Group for Pancreatic Cancer. Para-aortic lymph node metastasis was eligible for this trial if it could be included in the radiation field. Patients were excluded from the study if they had received prior therapy for pancreatic cancer or previous radiation therapy to the upper abdomen, and if they had a concomitant malignancy, active inflammatory bowel disease, active gastric/duodenal ulcer, mental disorder, or other severe concurrent disease. Patients were also excluded if they had direct invasion of a tumor into the mucosal surface of the gastrointestinal tract or had received a metal stent insertion as treatment for obstructive jaundice. The treatment protocol for the present study prepared by the planning committee for the clinical trial was reviewed and approved by the National Institute of Radiological Sciences Ethics Committee of Human Clinical Research, and all patients signed an informed consent form before the initiation of therapy.
Treatment protocol Eligible patients received C-ion RT with concurrent gemcitabine chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion on days 1, 8, and 15. Carbon ion RT was initiated on day 1, and the radiation fractions were fixed at 12 fractions over 3 weeks. The doses of C-ion RT and gemcitabine were gradually increased in the dose escalation trial. First, the dose of C-ion RT was fixed at 43.2 gray equivalent (GyE), and the dose of gemcitabine was increased from 400, to 700, to 1000 mg/m2. Subsequently, the gemcitabine was fixed at 1000 mg/m2, and the radiation dose was increased by 5% increments.
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Carbon ion radiation therapy All patients were positioned supine and prone with arms up in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized with a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan). A set of 2.5- or 5-mmthick nonecontrast-enhanced computed tomography (CT) images was taken for treatment planning under respiratory gating. The patients fasted at least 3 hours before CT scan. Three-dimensional treatment planning of C-ion RT was performed using the HIPLAN software program (National Institute of Radiological Sciences, Chiba, Japan) (4, 5). The gross tumor volume (GTV) was determined by CT, magnetic resonance imaging, and 18 fluoro-2-deoxyglucose positron emission tomography (18FDG-PET). The clinical target volume was defined as the GTV including a 5-mm margin and the locoregional elective nodal and neuroplexus region. The locoregional elective nodal regions, which were classified as N2 stations according to the General Rules for Cancer of the Pancreas published by the Japan Pancreas Society (6), included the celiac, superior mesenteric, peri-pancreatic, portal, and para-aortic region for pancreatic head cancer and the splenic region for pancreatic body and tail cancer. The planning target volume (PTV) included the clinical target volume with a 5-mm margin for possible positioning errors, respecting anatomic boundaries such as the stomach, duodenum, small intestine, and transverse colon. In cases in which the tumor was located close to critical organs, the margin was reduced accordingly. Although 4-dimensional CT was not required in all patients, the PTV expansion was customized using the information from organ motion analysis, which has been previously described (7). The maximal absolute doses that covered 1 cm3 of the stomach, duodenum, and spinal cord were approximately 50 GyE, 50 GyE, and 30 GyE, respectively. At least 95% of the GTV and 90% of the PTV received at least 95% of the prescribed dose. Field arrangements were generally designed using a 4-field plan. A typical dose distribution is shown in Figure 1. Carbon ion RT was carried out once per day, 4 days per week (Tuesday through Friday). One port was treated in each session. At every treatment session the patient’s position was verified with a computer-aided online positioning system using a 2-dimensional bone matching method. Respiratory gating was used in all patients and was the tracking method under free breathing. The doses of carbon ions are expressed in photon equivalent doses, which were defined as the physical doses multiplied by the relative biological effectiveness of the carbon ions (4). All patients fasted from at least 3 hours or more before C-ion RT.
Patient evaluation for toxicity and response Toxicity was classified according to the National Cancer Institute Common Toxicity Criteria (version 3.0). Doselimiting toxicity (DLT) was defined as any of following
C-ion RT with GEM for LAPC
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within 90 days from the start of C-ion RT with gemcitabine: grade 3 febrile hematologic toxicity or grade 4 hematologic toxicity such as leukopenia, neutropenia, or thrombocytopenia; grade 3 nonhematologic toxicity excluding nausea/ vomiting, fatigue, dehydration, and anorexia not controlled by optimal supportive care; and grade 4 nonhematologic toxicity. Toxicities not caused by C-ion RT with gemcitabine were not classified as DLT; for example, cholangitis from a blocked biliary stent and symptoms related to tumor progression, such as pain or bowel obstruction. The patient cohorts consisted of a minimum of 3 patients at each dose level, and if 1 DLT was observed in any cohort then 3 additional patients were evaluated at the same level. If only 1 or 2 of these 6 patients experienced DLT, then the next level of the dose schedule would begin enrollment. If 3 or more patients experienced DLT at a given level, then the previous level would be considered the maximally tolerated dose (MTD). The increase of dose level was performed in agreement by the Working Group for Pancreatic Cancer. Tumor response was determined by comparing pretreatment and posttreatment CT scans and 18FDG-PET scans and was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). In addition, FDG accumulation was added for the judgment of tumor progression; that is, increasing FDG accumulation was assumed to be progressive disease even if it was stable disease according to RECIST. The residual accumulation 6 months after treatment was also assumed as a local failure.
Follow-up Patients were followed up using CT, 18FDG-PET scans, or upper gastrointestinal endoscopy at least every 6 months. Any other evaluations prompted by symptoms, laboratory evaluation results, or at the treating physicians’ discretion were also used to score events. All patients were followed without any anticancer treatment until they experienced disease progression.
Statistical analysis This trial was designed to characterize the toxicities incurred with escalating doses of C-ion RT with concurrent gemcitabine. The primary endpoint was to evaluate acute reactions in normal tissues and to determine the MTD. The secondary endpoint was to assess the late toxicity, freedom from local progression (FFLP), and overall survival (OS). Local recurrence was defined in terms of lesions occurring in the PTV according to CT or 18FDG-PET scans. The absence of local recurrence was described as FFLP, which indicated no evidence of increase in tumor size of >20% by CT and no accumulation by 18FDG-PET later than 6 months after treatment. Recurrent disease was diagnosed by imaging studies, and biopsy confirmation was not obtained. We calculated the FFLP and OS rates from the first day of C-ion RT using the Kaplan-Meier method.
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Fig. 1. Dose distribution on a computed tomography image for treatment planning. Isodose lines indicate the 95%, 90%, 70%, 48%, 30%, 20%, and 10% dose areas (from inside to outside). Planning target volume (yellow line) includes primary tumor, retroperitoneal neuroplexus, and prophylactic lymph node area. Target volume receives a higher dose, whereas organs at risk receive a lower dose. A color version of this figure is available at www.redjournal.org.
Results Patient characteristics Seventy-six patients were entered into the study between April 2007 and February 2012. Of these patients, 72 were clinically eligible for the study. Four patients were ineligible and excluded from the analyses because of liver metastases that became obvious before the administration of C-ion RT (nZ3) or the inadequacy of histologic confirmation (nZ1). The treated patients and tumor characteristics are listed in Table 1. The 7 cases with stage IV had para-aortic lymph node metastasis.
The toxicities in all patients are summarized in Table 3. One patient underwent C-ion RT alone because of prolonged obstructive jaundice and deterioration of his general condition. The other patients were able to complete the C-ion RT with gemcitabine schedule with the support of some medication.
Response rate and survival Seventy-one patients were evaluable for tumor response. The single patient who was treated with C-ion RT alone was excluded from this analysis. Local recurrence was observed in 17% of the patients by CT scan (RECIST criteria),
Toxicity
Table 1
Toxicities were evaluated in the 72 patients. With regard to hematologic toxicities, grade 3-4 neutropenia, leukopenia, or thrombopenia was observed in 38 patients (53%). Doselimiting toxicity was observed in 3 patients: grade 4 neutropenia in 2 patients who were prescribed 43.2 GyE and grade 3 intratumoral infection in 1 patient who was prescribed 50.4 GyE (Table 2). The other grade 3 nonhematologic toxicity observed was anorexia (7%). There were no cases showing life-threatening toxicity, and no treatment-related deaths occurred. Acute gastroduodenal ulcers of grade 1 or 2 were observed in 11 patients (15%); all recovered with conservative management. Six of 11 patients treated with 55.2 GyE developed grade 1 or 2 ulcers. No grade 3 or higher acute gastrointestinal ulcers were observed. One patient treated at the 50.4-GyE dose level experienced a late grade 3 gastric ulcer with hemorrhage 10 months after the C-ion RT. She was treated by endoscopic and interventional hemostatic therapy.
All patients Sex Male Female Age (y) ECOG PS 0 1 2 UICC stage III IV Tumor location Head Bodyetail Tumor size (cm3) Baseline CA19-9 (U/mL)
Patient and tumor characteristics
Characteristic
Value 72 49 (68) 23 (32) 63 (39-75) 14 (19) 55 (76) 3 (4) 65 (90) 7 (19) 38 34 14.8 263
(53) (47) (1.7-98.3) (0.2-24,170)
Abbreviations: ECOG PS Z Eastern Cooperative Oncology Group performance status; UICC Z Union for International Cancer Control. Values are number (percentage) or median (range).
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Table 2 Number of patients assigned to each dose level and dose-limiting toxicity
1 2 3 4 5 6 7 8
C-ion RT (GyE)
GEM (mg/m3)
No. of patients treated
43.2 43.2 43.2 45.6 48.0 50.4 52.8 55.2
400 700 1000 1000 1000 1000 1000 1000
6 6 12 7 8 11 11 11
No. (%) of DLT cases 0 0 2 (3) 0 1 (1) 0 0 0
Abbreviations: C-ion RT Z carbon ion radiation therapy; GEM Z gemcitabine.
Table 3
Toxicities of grade 2 or greater Grade 2
Grade 3
Grade 4
Toxicity
n
%
n
%
n
%
Leukopenia Neutropenia Thrombocytopenia Anorexia GI ulcer/bleeding Infection
29 31 10 12 7 0
40 43 14 17 10
35 29 3 6 1 1
49 40 4 8 1 1
1 2 0 0 0 0
1 3
Abbreviation: GI Z gastrointestinal.
CT, negative findings on 18FDG-PET indicated that there were no viable tumor cells. The most common distant failure sites were liver and peritoneum (73%). Of all patients, 61 patients (86%) experienced distant metastases. The median time to progression was 5.9 months.
Discussion This study did not identify the MTD. However, a dose greater than 55.2 GyE was not administered because of the possible occurrence of severe late toxicities due to C-ion RT. Among the patients who received a total dose of 55.2 GyE, the frequency of mild gastroduodenal ulcer was increased, and 1 patient who received 50.4 GyE experienced a late gastric ulcer and bleeding. We thus decided to suspend the dose escalation at the level of 55.2 GyE and observe the expression of late toxicity cautiously. In the last analysis, an additional severe late complication of the gastrointestinal tract was not found at any dose level during the more than 2-year follow-up. We concluded that 55.2 GyE with full-dose gemcitabine did not exceed the MTD. A novel finding in this study is that C-ion RT including subclinical lymph node areas was feasible even with concurrent full-dose gemcitabine without enhancing the risk of CT progression
100
Percent survival
whereas it was quite clear in 54% of the patients with the addition of an 18FDG-PET scan. The 18FDG accumulation accurately reflected the response of the primary lesion after C-ion RT. The 18FDG uptake on PET imaging decreased to a moderate extent by 1 month after C-ion RT and disappeared almost completely at the 6-month evaluations, even when the tumor size did not shrink. In cases of tumor recurrence, the 18FDG uptake increased in advance of the tumor increase in size. The 1- and 2-year FFLP rates were 92% (95% confidence interval [CI] 81%-96%) and 83% (95% CI 69%-92%) by CT criteria, and 63% (95% CI 49%74%) and 30% (95% CI 16%-45%) by 18FDG-PET criteria, respectively (Fig. 2). The median OS was 19.6 months (95% CI 16.5-23.5 months). The 1- and 2-year OS rates were 73% (95% CI 61%-82%) and 35% (95% CI 25%-46%) in all patients, respectively (Fig. 3a). Seven patients who had stage IV due to para-aortic lymph node metastases experienced distant metastases as initial failure sites and had significantly worse survival than patients with stage III (PZ.0001). In the high-dose group with stage III (45.6 GyE: nZ42), the 2-year FFLP rate, median OS, and 2-year OS rate were 40% (95% CI 24%-58%) by PET criteria, 23.9 months (95% CI 18.6-26.6 months), and 48% (95% CI 33%-62%), respectively. In contrast, in the low-dose group with stage III (43.2 GyE: nZ22), the 2-year FFLP rate, median OS, and 2-year OS rate were 9% (95% CI 1%-43%) by PET criteria, 19.3 months (95% CI 16.5-23.5 months), and 23% (95% CI 10%-44%). The high-dose group had a tendency to show good long-term survival; however, there were no significant differences (PZ.067) (Fig. 3b). The patterns of initial disease progression were local recurrence in 21 patients, regional in 1 patient, distant in 43 patients, local and regional in 1 patient, and local and distant in 3 patients. Salvage surgery could be performed for 5 patients who experienced local recurrence. These 5 patients experienced local recurrence separated from the main artery approximately 1 year after C-ion RT. The early sign of recurrences could be detected by 18FDG-PET. Although soft tissue around the main artery, which was considered fibrotic change, did not entirely disappear by
Dose level
5
C-ion RT with GEM for LAPC
PET progression
80 60 40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
Fig. 2. Kaplan-Meier estimates of freedom from local progression. Abbreviations: C-ion RT Z carbon ion radiation therapy; CT Z computed tomography; PET Z positron emission tomography.
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b
43.2GyE (n=22)
100
45.6-55.2GyE (n=42)
80
Percent survival
Percent survival
a 100 60 40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
80 60
P=.067
40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
Fig. 3. Kaplan-Meier estimates of overall survival in all patients (a) and according to patient groups stratified by irradiated dose in stage III patients (b). Abbreviation: C-ion RT Z carbon ion radiation therapy. intolerable toxicities. A grade 3 or greater gastrointestinal ulcer was observed in only 1 patient (1%). This is less than the incidence reported in a recent phase 1/2 trial of gemcitabineeconcurrent proton radiation therapy (10%) and intensity modulated radiation (8%) for LAPC (8, 9). On the basis of prior clinical experience, we contend that concurrent use of gemcitabine with photon radiation therapy must sacrifice either the systemic intensity of gemcitabine or the locoregional coverage in the radiation field. Ikeda et al (10) found in a phase 1 gemcitabine dose escalation trial with conventional photon radiation therapy that the maximum tolerated dose of weekly gemcitabine was 250 mg/m2. A subsequent phase 2 trial showed that the pattern of failure was distant metastases in 97% of the patients, and the 1-year survival rate was 28% (11). It is apparent that the maximal systemic effect is essential in the management of LAPC, because this cancer is dominated by distant metastatic spread. To address this problem, McGinn et al (12) elected to irradiate the primary tumor alone, excluding normalappearing regional lymph nodes. This was based on the assumption that the majority of the benefit from radiation would result from control of the primary tumor, rather than control of subclinical disease in these nodes. Several studies indicate that the omission of prophylactic lymph node irradiation did not result in an excess of marginal failures (13, 14). However, these data were based on a small number of patients, and the follow-up period was very short because many patients experienced clinical failure by metastatic spread over several months. In fact, locoregional recurrence is a major mode of treatment failure in both resected and unresected pancreatic cancer cases (15, 16). According to a pooled analysis of 5954 pancreatic cancer patients who underwent radical surgical resection, the probability of metastasis in regional lymph nodes was estimated to be 59% to 86.4% (17). In addition, regional metastasis to lymph nodes in unresectable LAPC may be more extensive than in resectable cases. Though the use of radiation therapy for the elective treatment of regional lymph nodes is controversial, powerful locoregional and systemic control with C-ion RT plus full-dose gemcitabine were thought to contribute to survival benefit.
Recently, advanced radiation techniques were adapted to the treatment of LAPC; however, FFLP rates were poor, and it is not clear whether a survival benefit has been achieved. Ben-Josef et al (9) reported that 2-year FFLP was 59% and MST was 14.8 months in a dose escalation study of intensity modulated radiation therapy. Others have also documented poor local control (20% at 2 years) with conventional photon radiation therapy (14). Recent reports of intensity modulated radiation therapy, stereotactic radiation therapy, and proton therapy documented only short-term outcomes and did not achieve a survival advantage (8, 9, 18). Carbon ion RT might contribute to prolong survival, with physical and biological advantages over low linear energy transfer radiation therapy. We found that there was a discrepancy between the evaluation using CT criteria and 18FDG-PET criteria, which could assess the tumor viability more precisely. One reason for this could be the difficulty in assessing local disease using the current imaging technology. Anatomic imaging such as CT is usually applicable to the analysis of tumor effect. However, these modalities have limitations that include treatment-related fibrosis and a strong desmoplastic background typical of pancreatic cancer, as opposed to functional imaging such as 18FDG-PET (14, 19). We have to pay attention that the local failure rates after radiation therapy could be underestimated. In summary, our results indicate that C-ion RT with concurrent full-dose gemcitabine was well tolerable and effective in patients with unresectable LAPC. The extremely low and manageable toxicity profiles suggest that a further dose escalation study may be warranted. Intensive local therapy and full-dose systemic therapy might improve the outcome of patients with LAPC.
References 1. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-2413.
Volume - Number - 2016 2. Ishii H, Furuse J, Boku N, et al. Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506. Jpn J Clin Oncol 2010;40:573-579. 3. Wolff RA, Evans DB, Gravel DM, et al. Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 2001;7:2246-2253. 4. Kanai T, Endo M, Minohara S, et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys 1999;44:201-210. 5. Kanai T, Furusawa Y, Fukutsu K, et al. Irradiation of mixed beam and design of spread-out bragg peak for heavy-ion radiotherapy. Radiat Res 1997;147:78-85. 6. Society JP. Classification of Pancreatic Carcinoma (English Edition). 3rd ed. Tokyo: Kanehara; 2011. 7. Mori S, Hara R, Yanagi T, et al. Four-dimensional measurement of intrafractional respiratory motion of pancreatic tumors using a 256 multi-slice CT scanner. Radiother Oncol 2009;92:231-237. 8. Terashima K, Demizu Y, Hashimoto N, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol 2012; 103:25-31. 9. Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;84: 1166-1171. 10. Ikeda M, Okada S, Tokuuye K, et al. A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Br J Cancer 2002;86:1551-1554.
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11. Okusaka T, Ito Y, Ueno H, et al. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 2004;91:673-677. 12. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2001;19:42024208. 13. Kawakami H, Uno T, Isobe K, et al. Toxicities and effects of involvedfield irradiation with concurrent cisplatin for unresectable carcinoma of the pancreas. Int J Radiat Oncol Biol Phys 2005;62:1357-1362. 14. Murphy JD, Adusumilli S, Griffith KA, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2007;68:801-808. 15. Westerdahl J, Andren-Sandberg A, Ihse I. Recurrence of exocrine pancreatic cancerelocal or hepatic? Hepatogastroenterology 1993;40: 384-387. 16. Nitecki SS, Sarr MG, Colby TV, et al. Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221:59-66. 17. Sun W, Leong CN, Zhang Z, et al. Proposing the lymphatic target volume for elective radiation therapy for pancreatic cancer: A pooled analysis of clinical evidence. Radiat Oncol 2010;5:28. 18. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multiinstitutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer 2015;121:1128-1137. 19. Rothenberg ML, Abbruzzese JL, Moore M, et al. A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma. Cancer 1996;78:627-632.
Radiation Oncology biology
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Clinical Investigation
Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer Makoto Shinoto, MD,*,y,z Shigeru Yamada, MD, PhD,* Kotaro Terashima, MD, PhD,z Shigeo Yasuda, MD, PhD,* Yoshiyuki Shioyama, MD, PhD,y Hiroshi Honda, MD, PhD,z Tadashi Kamada, MD, PhD,* Hirohiko Tsujii, MD, PhD,* and Hiromitsu Saisho, MD, PhD,x the Working Group for Pancreas Cancer *Hospital of Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan; yIon Beam Therapy Center, SAGA HIMAT Foundation, Tosu, Japan; z Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and xDepartment of Internal Medicine and Clinical Oncology, Kaken Hospital, Chemotherapy Research Institute, Chiba, Japan Received Sep 17, 2015, and in revised form Dec 14, 2015. Accepted for publication Dec 15, 2015.
Summary Carbon ion radiation therapy is a unique external radiation therapy that has an excellent dose conformity and higher biological effectiveness compared with conventional radiation therapy. We performed a dose escalation study of carbon ion radiation therapy plus concurrent gemcitabine in 72 patients with locally advanced
Purpose: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m2 under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. Results: Seventy-six patients were enrolled. Among the 72 treated patients, doselimiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion
Reprint requests to: Makoto Shinoto, MD, SAGA HIMAT Foundation, Ion Beam Therapy Center, 3049 harakoga-machi, Tosu, Saga, 841-0071 Japan. Tel: (þ81) 942-81-1897; E-mail: [email protected] This study was supported by the Research Project with Heavy Ions at the National Institute of Radiological Sciences-Heavy Ion Medical Accelerator in Chiba. Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e7, 2016 0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.12.362
AcknowledgmentdThe authors thank the members of The Working Group for Pancreatic Cancer, Takehide Asano, Taketo Yamaguchi, Hodaka Amano, Takeshi Ishihara, Masayuki Otsuka, Masamichi Matsuda, Osamu Kainuma, Akihiro Funakoshi, Junji Furuse, Toshio Nakagori, Takuji Okusaka, Hiroshi Ishii, Tatsuya Nagakawa, Shinichiro Takahashi, Shoichi Hishinuma, Masafumi Nakamura, Hirofumi Saito, Kiyoshi Ohara, Shinichi Ohkawa, and Masahiro Hiraoka, for their constructive discussion and precious advice.
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pancreatic cancer. Carbon ion radiation therapy with full-dose gemcitabine was considered well tolerated and effective.
RT was found to be 1000 mg/m2. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m2) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (45.6 GyE) were 35% and 48%, respectively. Conclusions: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer. Ó 2016 Elsevier Inc. All rights reserved.
Introduction Pancreatic cancer is one of the most lethal cancers, and it is the fourth leading cause of death from cancer in Japan. At this time surgery is the only path to cure, but only a small number of patients present with resectable disease at the time of diagnosis. The majority of patients present with advanced unresectable disease. After the introduction of gemcitabine as a key drug, the prognosis for patients with pancreatic cancer improved slightly (1, 2). In localized pancreatic cancer, local control using radiation therapy is expected to have an impact on survival. However, radiation therapy has often been used suboptimally in pancreatic cancer. The sensitivity of the organs in the upper abdomen has limited the radiation dose to levels that are ineffective against gross disease. In addition, gemcitabine is a potent radiation sensitizer, and its concurrent use with radiation therapy has been limited by toxicity (3). Compared with photon beams, carbon ion beams offer improved dose distribution, enabling us to concentrate a sufficient dose within a target volume while minimizing the dose in the surrounding normal tissue. In addition, carbon ions (being heavier than protons) provide greater biological effectiveness, which increases with depth, reaching the maximum at the end of the beam’s range. This is an ideal property of cancer therapy in which a local type of therapy, such as carbon ion radiation therapy (C-ion RT), is needed. Thus, we hypothesized that an intensification of local therapy using C-ion RT combined with systemic therapy using gemcitabine would result in better local control and survival for locally advanced pancreatic cancer (LAPC). We performed a dose escalation study to determine the maximum tolerated C-ion RT and gemcitabine dose delivered concurrently and to estimate the local effect and survival with this regimen.
Methods and Materials Patient eligibility Patients were eligible for this study if they fulfilled the following criteria: histologically or cytologically confirmed invasive ductal carcinomas of the pancreas with unresectable LAPC; presence of either measurable or evaluable
disease, but the lesion does not exceed 15 cm in diameter; age 75 years or younger; Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate organ function, defined as an absolute leukocyte count 4000/ mm3, platelet count 100,000/mm3, hemoglobin 10 g/ dL, serum creatinine 1.5 mg/dL, creatinine clearance 60 mL/min, serum bilirubin 2.0, and serum aspartate aminotransferase and alanine aminotransferase 2.5 times the upper limit of normal range for the institution. Unresectability was defined by radiographic evidence of encasement of the celiac axis, the superior mesenteric artery, or both (involving 180 ) or by occlusion of the superior mesenteric vein, portal vein, or both confluences, which were reviewed by the Working Group for Pancreatic Cancer. Para-aortic lymph node metastasis was eligible for this trial if it could be included in the radiation field. Patients were excluded from the study if they had received prior therapy for pancreatic cancer or previous radiation therapy to the upper abdomen, and if they had a concomitant malignancy, active inflammatory bowel disease, active gastric/duodenal ulcer, mental disorder, or other severe concurrent disease. Patients were also excluded if they had direct invasion of a tumor into the mucosal surface of the gastrointestinal tract or had received a metal stent insertion as treatment for obstructive jaundice. The treatment protocol for the present study prepared by the planning committee for the clinical trial was reviewed and approved by the National Institute of Radiological Sciences Ethics Committee of Human Clinical Research, and all patients signed an informed consent form before the initiation of therapy.
Treatment protocol Eligible patients received C-ion RT with concurrent gemcitabine chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion on days 1, 8, and 15. Carbon ion RT was initiated on day 1, and the radiation fractions were fixed at 12 fractions over 3 weeks. The doses of C-ion RT and gemcitabine were gradually increased in the dose escalation trial. First, the dose of C-ion RT was fixed at 43.2 gray equivalent (GyE), and the dose of gemcitabine was increased from 400, to 700, to 1000 mg/m2. Subsequently, the gemcitabine was fixed at 1000 mg/m2, and the radiation dose was increased by 5% increments.
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Carbon ion radiation therapy All patients were positioned supine and prone with arms up in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized with a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan). A set of 2.5- or 5-mmthick nonecontrast-enhanced computed tomography (CT) images was taken for treatment planning under respiratory gating. The patients fasted at least 3 hours before CT scan. Three-dimensional treatment planning of C-ion RT was performed using the HIPLAN software program (National Institute of Radiological Sciences, Chiba, Japan) (4, 5). The gross tumor volume (GTV) was determined by CT, magnetic resonance imaging, and 18 fluoro-2-deoxyglucose positron emission tomography (18FDG-PET). The clinical target volume was defined as the GTV including a 5-mm margin and the locoregional elective nodal and neuroplexus region. The locoregional elective nodal regions, which were classified as N2 stations according to the General Rules for Cancer of the Pancreas published by the Japan Pancreas Society (6), included the celiac, superior mesenteric, peri-pancreatic, portal, and para-aortic region for pancreatic head cancer and the splenic region for pancreatic body and tail cancer. The planning target volume (PTV) included the clinical target volume with a 5-mm margin for possible positioning errors, respecting anatomic boundaries such as the stomach, duodenum, small intestine, and transverse colon. In cases in which the tumor was located close to critical organs, the margin was reduced accordingly. Although 4-dimensional CT was not required in all patients, the PTV expansion was customized using the information from organ motion analysis, which has been previously described (7). The maximal absolute doses that covered 1 cm3 of the stomach, duodenum, and spinal cord were approximately 50 GyE, 50 GyE, and 30 GyE, respectively. At least 95% of the GTV and 90% of the PTV received at least 95% of the prescribed dose. Field arrangements were generally designed using a 4-field plan. A typical dose distribution is shown in Figure 1. Carbon ion RT was carried out once per day, 4 days per week (Tuesday through Friday). One port was treated in each session. At every treatment session the patient’s position was verified with a computer-aided online positioning system using a 2-dimensional bone matching method. Respiratory gating was used in all patients and was the tracking method under free breathing. The doses of carbon ions are expressed in photon equivalent doses, which were defined as the physical doses multiplied by the relative biological effectiveness of the carbon ions (4). All patients fasted from at least 3 hours or more before C-ion RT.
Patient evaluation for toxicity and response Toxicity was classified according to the National Cancer Institute Common Toxicity Criteria (version 3.0). Doselimiting toxicity (DLT) was defined as any of following
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within 90 days from the start of C-ion RT with gemcitabine: grade 3 febrile hematologic toxicity or grade 4 hematologic toxicity such as leukopenia, neutropenia, or thrombocytopenia; grade 3 nonhematologic toxicity excluding nausea/ vomiting, fatigue, dehydration, and anorexia not controlled by optimal supportive care; and grade 4 nonhematologic toxicity. Toxicities not caused by C-ion RT with gemcitabine were not classified as DLT; for example, cholangitis from a blocked biliary stent and symptoms related to tumor progression, such as pain or bowel obstruction. The patient cohorts consisted of a minimum of 3 patients at each dose level, and if 1 DLT was observed in any cohort then 3 additional patients were evaluated at the same level. If only 1 or 2 of these 6 patients experienced DLT, then the next level of the dose schedule would begin enrollment. If 3 or more patients experienced DLT at a given level, then the previous level would be considered the maximally tolerated dose (MTD). The increase of dose level was performed in agreement by the Working Group for Pancreatic Cancer. Tumor response was determined by comparing pretreatment and posttreatment CT scans and 18FDG-PET scans and was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). In addition, FDG accumulation was added for the judgment of tumor progression; that is, increasing FDG accumulation was assumed to be progressive disease even if it was stable disease according to RECIST. The residual accumulation 6 months after treatment was also assumed as a local failure.
Follow-up Patients were followed up using CT, 18FDG-PET scans, or upper gastrointestinal endoscopy at least every 6 months. Any other evaluations prompted by symptoms, laboratory evaluation results, or at the treating physicians’ discretion were also used to score events. All patients were followed without any anticancer treatment until they experienced disease progression.
Statistical analysis This trial was designed to characterize the toxicities incurred with escalating doses of C-ion RT with concurrent gemcitabine. The primary endpoint was to evaluate acute reactions in normal tissues and to determine the MTD. The secondary endpoint was to assess the late toxicity, freedom from local progression (FFLP), and overall survival (OS). Local recurrence was defined in terms of lesions occurring in the PTV according to CT or 18FDG-PET scans. The absence of local recurrence was described as FFLP, which indicated no evidence of increase in tumor size of >20% by CT and no accumulation by 18FDG-PET later than 6 months after treatment. Recurrent disease was diagnosed by imaging studies, and biopsy confirmation was not obtained. We calculated the FFLP and OS rates from the first day of C-ion RT using the Kaplan-Meier method.
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Fig. 1. Dose distribution on a computed tomography image for treatment planning. Isodose lines indicate the 95%, 90%, 70%, 48%, 30%, 20%, and 10% dose areas (from inside to outside). Planning target volume (yellow line) includes primary tumor, retroperitoneal neuroplexus, and prophylactic lymph node area. Target volume receives a higher dose, whereas organs at risk receive a lower dose. A color version of this figure is available at www.redjournal.org.
Results Patient characteristics Seventy-six patients were entered into the study between April 2007 and February 2012. Of these patients, 72 were clinically eligible for the study. Four patients were ineligible and excluded from the analyses because of liver metastases that became obvious before the administration of C-ion RT (nZ3) or the inadequacy of histologic confirmation (nZ1). The treated patients and tumor characteristics are listed in Table 1. The 7 cases with stage IV had para-aortic lymph node metastasis.
The toxicities in all patients are summarized in Table 3. One patient underwent C-ion RT alone because of prolonged obstructive jaundice and deterioration of his general condition. The other patients were able to complete the C-ion RT with gemcitabine schedule with the support of some medication.
Response rate and survival Seventy-one patients were evaluable for tumor response. The single patient who was treated with C-ion RT alone was excluded from this analysis. Local recurrence was observed in 17% of the patients by CT scan (RECIST criteria),
Toxicity
Table 1
Toxicities were evaluated in the 72 patients. With regard to hematologic toxicities, grade 3-4 neutropenia, leukopenia, or thrombopenia was observed in 38 patients (53%). Doselimiting toxicity was observed in 3 patients: grade 4 neutropenia in 2 patients who were prescribed 43.2 GyE and grade 3 intratumoral infection in 1 patient who was prescribed 50.4 GyE (Table 2). The other grade 3 nonhematologic toxicity observed was anorexia (7%). There were no cases showing life-threatening toxicity, and no treatment-related deaths occurred. Acute gastroduodenal ulcers of grade 1 or 2 were observed in 11 patients (15%); all recovered with conservative management. Six of 11 patients treated with 55.2 GyE developed grade 1 or 2 ulcers. No grade 3 or higher acute gastrointestinal ulcers were observed. One patient treated at the 50.4-GyE dose level experienced a late grade 3 gastric ulcer with hemorrhage 10 months after the C-ion RT. She was treated by endoscopic and interventional hemostatic therapy.
All patients Sex Male Female Age (y) ECOG PS 0 1 2 UICC stage III IV Tumor location Head Bodyetail Tumor size (cm3) Baseline CA19-9 (U/mL)
Patient and tumor characteristics
Characteristic
Value 72 49 (68) 23 (32) 63 (39-75) 14 (19) 55 (76) 3 (4) 65 (90) 7 (19) 38 34 14.8 263
(53) (47) (1.7-98.3) (0.2-24,170)
Abbreviations: ECOG PS Z Eastern Cooperative Oncology Group performance status; UICC Z Union for International Cancer Control. Values are number (percentage) or median (range).
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Table 2 Number of patients assigned to each dose level and dose-limiting toxicity
1 2 3 4 5 6 7 8
C-ion RT (GyE)
GEM (mg/m3)
No. of patients treated
43.2 43.2 43.2 45.6 48.0 50.4 52.8 55.2
400 700 1000 1000 1000 1000 1000 1000
6 6 12 7 8 11 11 11
No. (%) of DLT cases 0 0 2 (3) 0 1 (1) 0 0 0
Abbreviations: C-ion RT Z carbon ion radiation therapy; GEM Z gemcitabine.
Table 3
Toxicities of grade 2 or greater Grade 2
Grade 3
Grade 4
Toxicity
n
%
n
%
n
%
Leukopenia Neutropenia Thrombocytopenia Anorexia GI ulcer/bleeding Infection
29 31 10 12 7 0
40 43 14 17 10
35 29 3 6 1 1
49 40 4 8 1 1
1 2 0 0 0 0
1 3
Abbreviation: GI Z gastrointestinal.
CT, negative findings on 18FDG-PET indicated that there were no viable tumor cells. The most common distant failure sites were liver and peritoneum (73%). Of all patients, 61 patients (86%) experienced distant metastases. The median time to progression was 5.9 months.
Discussion This study did not identify the MTD. However, a dose greater than 55.2 GyE was not administered because of the possible occurrence of severe late toxicities due to C-ion RT. Among the patients who received a total dose of 55.2 GyE, the frequency of mild gastroduodenal ulcer was increased, and 1 patient who received 50.4 GyE experienced a late gastric ulcer and bleeding. We thus decided to suspend the dose escalation at the level of 55.2 GyE and observe the expression of late toxicity cautiously. In the last analysis, an additional severe late complication of the gastrointestinal tract was not found at any dose level during the more than 2-year follow-up. We concluded that 55.2 GyE with full-dose gemcitabine did not exceed the MTD. A novel finding in this study is that C-ion RT including subclinical lymph node areas was feasible even with concurrent full-dose gemcitabine without enhancing the risk of CT progression
100
Percent survival
whereas it was quite clear in 54% of the patients with the addition of an 18FDG-PET scan. The 18FDG accumulation accurately reflected the response of the primary lesion after C-ion RT. The 18FDG uptake on PET imaging decreased to a moderate extent by 1 month after C-ion RT and disappeared almost completely at the 6-month evaluations, even when the tumor size did not shrink. In cases of tumor recurrence, the 18FDG uptake increased in advance of the tumor increase in size. The 1- and 2-year FFLP rates were 92% (95% confidence interval [CI] 81%-96%) and 83% (95% CI 69%-92%) by CT criteria, and 63% (95% CI 49%74%) and 30% (95% CI 16%-45%) by 18FDG-PET criteria, respectively (Fig. 2). The median OS was 19.6 months (95% CI 16.5-23.5 months). The 1- and 2-year OS rates were 73% (95% CI 61%-82%) and 35% (95% CI 25%-46%) in all patients, respectively (Fig. 3a). Seven patients who had stage IV due to para-aortic lymph node metastases experienced distant metastases as initial failure sites and had significantly worse survival than patients with stage III (PZ.0001). In the high-dose group with stage III (45.6 GyE: nZ42), the 2-year FFLP rate, median OS, and 2-year OS rate were 40% (95% CI 24%-58%) by PET criteria, 23.9 months (95% CI 18.6-26.6 months), and 48% (95% CI 33%-62%), respectively. In contrast, in the low-dose group with stage III (43.2 GyE: nZ22), the 2-year FFLP rate, median OS, and 2-year OS rate were 9% (95% CI 1%-43%) by PET criteria, 19.3 months (95% CI 16.5-23.5 months), and 23% (95% CI 10%-44%). The high-dose group had a tendency to show good long-term survival; however, there were no significant differences (PZ.067) (Fig. 3b). The patterns of initial disease progression were local recurrence in 21 patients, regional in 1 patient, distant in 43 patients, local and regional in 1 patient, and local and distant in 3 patients. Salvage surgery could be performed for 5 patients who experienced local recurrence. These 5 patients experienced local recurrence separated from the main artery approximately 1 year after C-ion RT. The early sign of recurrences could be detected by 18FDG-PET. Although soft tissue around the main artery, which was considered fibrotic change, did not entirely disappear by
Dose level
5
C-ion RT with GEM for LAPC
PET progression
80 60 40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
Fig. 2. Kaplan-Meier estimates of freedom from local progression. Abbreviations: C-ion RT Z carbon ion radiation therapy; CT Z computed tomography; PET Z positron emission tomography.
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b
43.2GyE (n=22)
100
45.6-55.2GyE (n=42)
80
Percent survival
Percent survival
a 100 60 40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
80 60
P=.067
40 20 0 0
12
24
36
48
60
Time from C-ion RT (months)
Fig. 3. Kaplan-Meier estimates of overall survival in all patients (a) and according to patient groups stratified by irradiated dose in stage III patients (b). Abbreviation: C-ion RT Z carbon ion radiation therapy. intolerable toxicities. A grade 3 or greater gastrointestinal ulcer was observed in only 1 patient (1%). This is less than the incidence reported in a recent phase 1/2 trial of gemcitabineeconcurrent proton radiation therapy (10%) and intensity modulated radiation (8%) for LAPC (8, 9). On the basis of prior clinical experience, we contend that concurrent use of gemcitabine with photon radiation therapy must sacrifice either the systemic intensity of gemcitabine or the locoregional coverage in the radiation field. Ikeda et al (10) found in a phase 1 gemcitabine dose escalation trial with conventional photon radiation therapy that the maximum tolerated dose of weekly gemcitabine was 250 mg/m2. A subsequent phase 2 trial showed that the pattern of failure was distant metastases in 97% of the patients, and the 1-year survival rate was 28% (11). It is apparent that the maximal systemic effect is essential in the management of LAPC, because this cancer is dominated by distant metastatic spread. To address this problem, McGinn et al (12) elected to irradiate the primary tumor alone, excluding normalappearing regional lymph nodes. This was based on the assumption that the majority of the benefit from radiation would result from control of the primary tumor, rather than control of subclinical disease in these nodes. Several studies indicate that the omission of prophylactic lymph node irradiation did not result in an excess of marginal failures (13, 14). However, these data were based on a small number of patients, and the follow-up period was very short because many patients experienced clinical failure by metastatic spread over several months. In fact, locoregional recurrence is a major mode of treatment failure in both resected and unresected pancreatic cancer cases (15, 16). According to a pooled analysis of 5954 pancreatic cancer patients who underwent radical surgical resection, the probability of metastasis in regional lymph nodes was estimated to be 59% to 86.4% (17). In addition, regional metastasis to lymph nodes in unresectable LAPC may be more extensive than in resectable cases. Though the use of radiation therapy for the elective treatment of regional lymph nodes is controversial, powerful locoregional and systemic control with C-ion RT plus full-dose gemcitabine were thought to contribute to survival benefit.
Recently, advanced radiation techniques were adapted to the treatment of LAPC; however, FFLP rates were poor, and it is not clear whether a survival benefit has been achieved. Ben-Josef et al (9) reported that 2-year FFLP was 59% and MST was 14.8 months in a dose escalation study of intensity modulated radiation therapy. Others have also documented poor local control (20% at 2 years) with conventional photon radiation therapy (14). Recent reports of intensity modulated radiation therapy, stereotactic radiation therapy, and proton therapy documented only short-term outcomes and did not achieve a survival advantage (8, 9, 18). Carbon ion RT might contribute to prolong survival, with physical and biological advantages over low linear energy transfer radiation therapy. We found that there was a discrepancy between the evaluation using CT criteria and 18FDG-PET criteria, which could assess the tumor viability more precisely. One reason for this could be the difficulty in assessing local disease using the current imaging technology. Anatomic imaging such as CT is usually applicable to the analysis of tumor effect. However, these modalities have limitations that include treatment-related fibrosis and a strong desmoplastic background typical of pancreatic cancer, as opposed to functional imaging such as 18FDG-PET (14, 19). We have to pay attention that the local failure rates after radiation therapy could be underestimated. In summary, our results indicate that C-ion RT with concurrent full-dose gemcitabine was well tolerable and effective in patients with unresectable LAPC. The extremely low and manageable toxicity profiles suggest that a further dose escalation study may be warranted. Intensive local therapy and full-dose systemic therapy might improve the outcome of patients with LAPC.
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